Ionis' Latest Attempt To Weaponize Antisense Against Cancer

| About: Ionis Pharmaceuticals, (IONS)

Summary

Cancer-causing mutations in the KRAS gene have been studied for 30 years yet no direct inhibitor of mutant KRAS enzyme has entered clinical trials.

Earlier generation antisense against cancer targets have not emerged from clinical trials. Most of those targets were upregulated in but not drivers of various cancers. KRAS mutations are cancer drivers.

IONIS-KRAS-2.5 Rx alias AZD4785 was able to "knock down" mutated KRAS potently and specifically in a preclinical study, reviving hopes for an effective weapon against this "undruggable" protein target.

Each discovery of a key cancer target is a potential catalyst of Ionis growth, and the longer that target remains undruggable by other means, the greater is Ionis' opportunity.

Recent elucidation of the identity and biology of primary driver mutation, H3K27M, of deadly, childhood diffuse intrinsic pontine glioma is a prime example. Other undruggable targets await ASO knockdown.

Ionis (NASDAQ:IONS) quietly added KRAS-mutant cancers to its list of generation 2.5 ASO (antisense oligonucleotide) targets. I say 'quietly' because IONIS-KRAS-2.5 Rx appeared in 2016 at the bottom of its preclinical pipeline, and was tagged only once among the 2016 Ionis press releases as "New Drug to Treat Cancer". And quietly because management knows many skeptical observers already see largesse in its pipeline.

Skeptics will say that IONIS-KRAS-2.5 Rx is a long shot because IONS's other cancer-related targets (H-ras, survivin, clusterin, Hsp27, eIF-4E) in development over the past two decades have yet to emerge from clinical trials that are now in the hands - and wallets - of numerous partners. Expectations are low, but choosing the right targets is the most important 1st step, just as in planning a military mission, and in retrospect, these were probably not the best targets.

KRAS is one of the most frequently mutated and lethal genes in cancer: like pancreas, lung and colon.

Mutated KRAS can be the primary driver of adenocarcinomas in these organs, and has been driving smart drug designers crazy. More than 30 years after its discovery, the enzyme for which the KRAS gene codes remains an "undruggable" target (see Ledford, 2015; Campbell, 2016). The Kras protein has been so difficult to target that developers have intentionally gone off-target to the related MEK-pathway with drugs like Mekinist® (NYSE:NVS) and selumetinib alias AZD6244 . One of the most recent strategies reported by top cancer center Memorial Sloan Kettering is to attack not one but two accessory pathways (Manchado, 2016) in KRAS-mutant lung cancer. Such approaches are regarded as "mutation-specific" but they are not sequence-specific and that is an important difference. The DNA sequence of normal KRAS and some of the nastiest mutants are known (see footnote) and theoretically addressable with a sequence specific ASO for each mutation.

Designated AZD4785 by partner AstraZeneca (NYSE:AZN), the new ASO looked potent and specific in a preclinical study presented at a 2016 NCRI poster session in the UK.

(Update: 3/16/17, 2.23 PM) How specific is not mentioned in the published report. The press release cited above indicates that the ASO "targets KRAS, regardless of mutation type" which implies it is not entirely sequence specific and that normal wild-type KRAS might also be knocked down.

Given the importance of KRAS and the tremendous efforts to tackle it, the sudden appearance of IONIS-KRAS-2.5 Rx in Ionis' pipeline in 2016 intrigues me. And AstraZeneca must be intrigued if willing pay IONS up to another $137 million for it.

Should AZD4785 prove effective against a common and deadly KRAS mutant, there could be a very large market for it. The appeal is sequence specificity: in theory, a properly constructed and effectively delivered antisense molecule will knock down the mutant gene and leave all other(s) including the unmutated allele (partner gene) untouched. Not that high specificity cannot eventually be achieved with a small drug inhibitor of mutant KRAS activity. Wellspring Biosciences is working on one, and has recently published preclinical results (Lito 2016). Investigators associated with Kite (NASDAQ:KITE) have successfully used ex vivo expanded, autologous tumor-infiltrating T lymphocytes specifically targeting mutant KRAS G12D in one patient (Tran 2016).

No drug - and there have been 200 trials - has proved effective for the tumor known as DIPG (Diffuse Intrinsic Pontine Glioma) which kills more children than any other type of brain tumor. Median survival is only 9 months, and 5-year survival is less than 1%. Even temozolomide, considered 1st line for other glioblastomas, is ineffective against DIPG (see here and in Grasso et al., 2015).

The primary driver mutation in DIPG has recently been identified and its biology elucidated. A mutation causing a single amino acid substitution (abbreviated K27M) in histone-3.3 causes widespread havoc in the entire epigenome of affected glial cells in the center of the brainstem (see Schwartzentruber 2012; Nikbakht 2016).

The most recent "mutation specific" drug to be trialed (phase 1) in children with H3K27M mutant DIPG is panobinostat (FARYDAK®, Novartis) which appeared effective in one preclinical study. But again, this drug is not sequence specific and is bound to have unintended consequences on the activity of multiple genes given its known mechanism of action. Antisense could be constructed to specifically target the mutant allele of the gene (called H3F3A) and hopefully leave the other allele as well as the 2nd H3.3 gene (called H3F3B) alone.

Rarely in drug discovery and development has there been a silver bullet that alone has successfully targeted an altered gene that is primary driver of a cancer's growth. Gleevec imatinib that targets Bcr-Abl kinase in Ph+ CML is an exception. Imbruvica for CLL is another. Ionis also has a platform that can spell exactly in the letters of the genetic code which gene to knock down. If it chooses the right gene targets - and a host of researchers would agree that KRAS is one - Ionis could permanently change the way the cancers it targets are managed.

The bull case for IONS is growth in revenues from from multiple sources, growth in partnerships, success in FDA approvals, its antisense platform, and in my opinion, its most recent and quietly added cancer target.

Bear case is what seems to be failure to prosecute other cancer targets over the years, and its balance sheet. The earnings deficits continue to accumulate; net current asset value has declined over the past four years from $416 million to ($15) million. Fortunes could of course improve with sales of Spinraza.

IONS stock has been volatile, surging upwards after the presidential election and the anncouncement that Spinraza had met primary endpoint at interim analysis of phase 3 CHERISH study. IONS has far outperformed the IBB but on Tuesday closed at the lower limit of the Bollinger band after that band had formed a neck in late February.

IONS constitutes 0.83% of the IBB in which it ranks #20, and I may make a comparable allocation to my portfolio. But having recently liquidated three of my four biotech holdings, I am reluctant without further study of the data on nusinersen and volanesorsen.

Footnote.

KRAS is pronounced 'K-rass' not 'crass.'

The DNA sequence of normal KRAS some of the nastiest mutations are known. Common examples: G12R and G12C where one amino acid (the 1st letter) is substituted for another (the 2nd) at position 12 in the protein. But substituting one amino acid of nearly 200 for another can impart malignant potential.

The un-mutated KRAS (proto-onco-) gene directs synthesis of an enzyme which can be switched on only as needed to control normal cell growth, then off again. The oncogene produces an incessantly active enzyme that drives cancerous growth.

KRAS can be genetically engineered into mouse pancreas to produce precancer. Additional mutations are required to cause invasive, cancerous growth (see Eser et al., 2014).

KRAS transgenes can also be used to model lung cancer, and shutting down mutant KRAS genes can cause tumor regression (see O'Hagan and Heyer, 2011). These mouse models help prove the importance of KRAS oncogene in human cancer and how important it is to design a method to switch it off or cut it out.

Bibliography

Brown et al. Strategy for "Detoxification" of a Cancer-Derived Histone Mutant Based on Mapping Its Interaction with the Methyltransferase PRC2. J Am Chem Soc 2014

Grasso et al. Functionally-defined Therapeutic Targets in Diffuse Intrinsic Pontine Glioma:A Report of the Children's Oncology Group DIPG Preclinical Consortium. Nat Med 2015

Eser et al. Oncogenic KRAS signalling in pancreatic cancer. British Journal of Cancer 2014

Hashizume et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nature Medicine 2014

Heinemann et al. Inhibition of demethylases by GSK-J1/J4. Nature 2012

Justin et al. Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2. Nature Comm 2016

Kruidenier et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 2012

Lito et al. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science 2016

Manchado et al. A combinatorial strategy for treating KRAS-mutant lung cancer. Nature 2016

Nikbakht et al. Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma. Nature Comm 2016

O'Hagan and Heyer. KRAS Mouse Models. Genes Cancer 2011

Ross et al. Targeting KRAS dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS. Abstracts for the NCRI Cancer Conferences 2016

Schwartzentruber et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 2012

Sunaga et al. Knockdown of Oncogenic KRAS in Non-Small Cell Lung Cancers Suppresses Tumor Growth and Sensitizes Tumor Cells. Mol Cancer Ther 2011

Tran et al. T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer. NEJM 2016

Disclosure: I/we have no positions in any stocks mentioned, but may initiate a long position in IONS over the next 72 hours.

I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

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